www.excemed.org
IMPROVING THE PATIENT’S LIFE THROUGH
MEDICAL EDUCATION
Preceptorship on Advances in Multiple Sclerosis (MS) and Neuro-Myelitis Optica (NMO)
6-8 July 2015 - Vancouver, Canada
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Advanced MRI
Shannon Kolind, PhD
Department of Medicine, Division of Neurology
University of British Columbia, Vancouver, BC, Canada
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Learning Objectives
1. Gain an overview of novel and advanced MRI techniques.
2. Understand the relative sensitivity and specificity of these MRI
techniques to various biological and pathological features.
3. Consider the use of MRI beyond anatomical assessment in
clinical trials for neurological disease therapies.
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Overview
Goal: To move beyond “conventional” MRI in clinical trials and even clinical
practice
• Example application: multiple sclerosis (MS)
• Example advanced MRI technique: myelin water
imaging
• Example clinical trial: Orchestra
• Introduction to other advanced MRI techniques in
Orchestra
• Summary of the sensitivity, specificity and
practicality of these advanced MRI techniques
d’Entremont and UBC team, ISMRM 2014
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Why move beyond conventional MRI in MS?
• Multiple Sclerosis involves
- Chronic inflammation
- Edema
- Gliosis
- Oligodendrocyte loss
- Axonal loss
- Demyelination
• Conventional images
- Lack specificity
- Lack sensitivity for non-lesional disease
- Are qualitative
• Clinical relevance
- Weak link between traditional imaging metrics & disability/progression
Same disability score
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Candidates for non-conventional MRI in neurological disease
• Myelin Water Imaging
• Magnetization transfer imaging
• Frequency shift imaging
(Susceptibility weighted imaging)
• Magnetic resonance spectroscopy
• Resting state functional MRI
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Myelin Water Imaging
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Myelin Water Imaging
Myelin water
Intra/Extra-cellular
(free) water
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Myelin Water Imaging
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Observed Spin Echo Signal
Intra / Extra Cellular
Water Signal
Myelin Water
Signal
Myelin water
Intra/ Extra-cellular (free)
water
Echo Time (ms)
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Myelin Water Imaging
Intra/extracellular (free) water
40-200ms
Myelin water
0-40ms Myelin Water
Fraction
=
+
Myelin Water
Fraction Map
MacKay, MRM 1994;31:673.
T2 (ms)
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Myelin Water Imaging
Laule, Neuroimage 2008;40:1575.
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Myelin Water Imaging
Meyers, MRI 2009;27:1096. Prasloski, Neuroimage 2012;63:533. Zhang, ISMRM 2015.
3D multi-echo T2
relaxation: 7 slices in
20 minutes
3D GRASE (combined
gradient and spin echo)
acquisition: 20 slices in
15 minutes
3D GRASE (optimized) acquisition: 20 slices
in under 8 minutes
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Myelin Water Imaging Applications
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Myelin Water Imaging in Primary Progressive MS
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Primary Progressive MS
• Primary Progressive MS (PPMS)
- More diffuse myelin and axonal damage
• Challenge:
- No approved therapies
- Current diagnostic markers based ineffective for clinical trials
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PPMS Myelin Reductions (Group Level)
Kolind, Neuroimage
2012;60:263.
R"R"
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Individual Patient Variations
Myelin Water Fraction
Control Average
Myelin Water Fraction
Control Standard Deviation
Kolind, Neuroimage
2012;60:263.
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Individual Patient Variations
4 02 -2 -4<-5.4(significant)
Kolind, Neuroimage
2012;60:263.
EDSS 1.5
4 2 0 -2 -4 Myelin Water Fraction
Z-score
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Individual Patient Variations
EDSS 1.5
EDSS 6.5
Kolind, Neuroimage
2012;60:263.
4 02 -2 -4<-5.4(significant)
Myelin Water Fraction
Z-score 4 2 0 -2 -4
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Localized Clinical Correlations with MWF in MS
Mental Functional System Score
Sensory Functional System Score
Kolind, Neuroimage 2012;60:263.
Correlation just below threshold (p < 0.07) Significant correlation (p < 0.05)
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Myelin Water Imaging in NMO and RRMS
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Neuromyelitis Optica
• Neuromyelitis optica (NMO)
- Was thought to be a subtype of MS
- Clinical similarities to relapsing remitting MS (RRMS)
- Focused on optic nerve and spinal cord
• Recent evidence revealed
- Antibody against a specific water channel
- Different mechanism of demyelination
• Challenges:
- Prognosis and treatment differ!
- Still controversial whether normal appearing tissue is affected in NMO
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Differentiating Between MS and NMO
Cervical Spinal Cord
Matthews, Kolind, in press.
Mye
lin W
ater
Fra
ctio
n
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Differentiating Between MS and NMO
Lesion mask Significantly reduced myelin water fraction (Z<-4)
Lesion mask Significantly reduced myelin water fraction (Z<-4)
M S patient: Age 33, EDSS 5, disease duration 50 months
NM O patient: Age 33, EDSS 4, disease duration 48 months
FLAIR
FLAIR
Matthews, Kolind, in press.
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Differentiating Between MS and NMO
Lesion mask Significantly reduced myelin water fraction (Z<-4)
Lesion mask Significantly reduced myelin water fraction (Z<-4)
M S patient: Age 33, EDSS 5, disease duration 50 months
NM O patient: Age 33, EDSS 4, disease duration 48 months
FLAIR
FLAIR
Matthews, Kolind, in press.
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Myelin Water Imaging in Motor Neuron Disease
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Motor Neuron Disease
• Characterised by progressive weakness with variable muscle wasting.
• Amyotrophic Lateral Sclerosis (ALS)
- Involves upper & lower motor neurons of brainstem and spinal anterior horns
- Median survival 2-3 years from symptom onset, but heterogeneous
• Primary Lateral Sclerosis (PLS)
- Involves only upper motor neurons
- Prolonged disease course (10-20 years)
- Takes 4 years for confident diagnosis
• Demyelination
- Is present
- Presumed secondary to axonal damage
- Not well studied
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Comparing Types of Motor Neuron Disease
0.05<p<0.10
Myelin water fraction reductions: PLS < Controls
p<0.05
Kolind, ALS & FTD 2013; 14:562.
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What’s Next?
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So far…
• We’ve shown that Myelin Water Imaging
- Detects differences in people with neurological disease
- Detects differences between neurological diseases
- Is sensitive to clinical measures
• What about…
- Changes over time?
- Effects of treatment?
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UBC Orchestra Advanced MRI Substudy
• “Advanced MRI measures of repair in Ocrelizumab treated patients”
• AIM
- To demonstrate…
- Repair (remyelination)
- Neuroprotection (normal appearing brain tissue myelin and axon stability)
• HYPOTHESES
- Ocrelizumab is superior to interferon (RRMS) and placebo (PPMS) on all
advanced MRI outcomes
• ADDITIONAL AIMS
- Assess relationship between advanced MRI outcomes and clinical scores
- Understand interplay between various advanced MRI techniques
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Advanced MRI in Orchestra Substudy
• Myelin Water Imaging
• Magnetization transfer imaging
• Frequency shift imaging
(Susceptibility weighted imaging)
• Magnetic resonance spectroscopy
• Resting state functional MRI
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Magnetization Transfer Imaging
=
-
• Based on magnetization
interaction between:
- Bulk water protons
- Macromolecular protons
• Magnetization transfer ratio
(MTR) affected by…
- Demyelination
- Remyelination
- Axonal damage
- Macrophage infiltration
- Activated microglia
- Inflammation / Edema
• Measure of “badness”
MTR
M0 Msat
M0
%
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Magnetic Resonance Spectroscopy
• Measures the concentrations
of brain metabolites
• N-acetylaspartate (NAA)
- Neurons and
oligodendrocytes
• Choline (Cho)
- Cell membranes
• Creatine (Cr)
- Energy storage
• Glutamate (Glu)
- Neurotransmitter
• Myo-Inositol (mI)
- Glial cells
NAA
Lactate
Glu Gln NAA
Cr
Cho
mI
Cr
mI
Glu
Gln
Dr Erin MacMillan
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Frequency Shift Imaging
• MRI data has magnitude and
phase
• Frequency shift calculated
from phase data
• Frequency shifts influenced by
- Iron
- Tissue microstructure
- Myelin
• Acquisition:
- Fast, high resolution
gradient echo scan
FLAIR
T1W Post-gad
Frequency Shift
Vanessa Wiggermann, Dr Alex Rauscher
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Resting State Functional MRI
• rs-fMRI
- Sensitive to plastic and degenerative changes in functional architecture
- Measures the pathological effects of MS beyond focal damage.
Suejin Lin, Dr Martin McKeown
MS Group Control Group
Connectivity
Map
Lin, ECTRIMS 2014:P538. Lin, AAN 2015.
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Advanced MRI in Substudy – Take Home
• Myelin Water Imaging
- Very specific
• Magnetization transfer imaging
- Sensitive but less specific
• Frequency shift imaging
- Sensitive but less specific, very
high resolution, practical
• Magnetic resonance
spectroscopy
- Metabolite specific, but limited
resolution/coverage
• Resting state functional MRI
- May provide complementary
functional information
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Concluding Remarks
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Working Toward Unconventional MRI in Clinical Trials and Clinical Practice
• Current projects include:
- Clinical trials in MS and NMO
- Applications to stroke, PD, and brain and spinal cord injury
- Combining structural imaging with functional imaging and cognition
- Developing more new sensitive and specific biomarkers with MRI
• Still be done:
- Understand all imaging parameters and their use in research & practice
- Show the predictive power of these techniques for disease progression
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Acknowledgments
University of British Columbia
Tony Traboulsee
Alex MacKay
David Li
Irene Vavasour
Erin MacMillan
Roger Tam
Yinshan Zhao
Alex Rauscher
Linda Chandler
Aaron Khung
Laura Harvey
Andrew Riddehough
Trudy Harris
Laura Barlow
Corree Laule
Martin McKeown
Rob Carruthers
Wayne Moore
Katrina McMullen
Emil Ljungberg
Anna Combes
Praveena Manogaran
Youngjin Yoo
Saurabh Garg
Alice Lee
Julia Schubert
Suejin Lin
Sandra Meyers
Emma Eberts
Lisa Tang
Vanessa Wiggermann
Jing Zhang
Rita Gorodezky
Anna Bley
Elisabeth Baumann
Clara Tabea Strunk
Shuhan Xiao
Anika Wurl
Funding
Milan &
Maureen Ilich
Foundation,
Roche,
Genzyme,
Chugai,
iCord,
Michael Smith
Foundation for
Health
Research,
MS Society of
Canada
Volunteers and their families
Our MR technologists
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Summary of Candidates for Non-Conventional MRI in Neurological Disease
TECHNIQUE SENSITIVE TO PRACTICALITY FOR CLINICAL
TRIALS Multi-Spin Echo Myelin Water
Imaging (MWF) myelin (intact and debris)
not yet available as product sequence
mcDESPOT (fM) myelin, water content acquisition more commonly
available but complicated analysis
Magnetization Transfer Imaging (MTR)
water content, axons, myelin, other macromolecules
commonly available but not standardized, varies between
vendors
Frequency Shift Imaging (fs) iron, tissue microstructure,
myelin, water content commonly available
Magnetic Resonance Spectroscopy (Cho, free lipids)
metabolites commonly available but limited resolution/volumetric coverage
Resting State Functional MRI (connectivity)
connectivity, motion commonly available acquisition but not standardized, analysis
highly variable
Dr Corree Laule, Dr David Li, Dr Alex MacKay, Dr Irene Vavasour, Dr Tony Traboulsee, Dr Alex Rauscher, Dr Shannon Kolind.